Chemical Synthesis of Bioactive Diterpenoids

生物活性二萜类化合物的化学合成

• 批准号: 10405930
• 负责人: Christopher D Vanderwal
• 金额: $ 42.86万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405930
• 关键词: Address; Anti-Bacterial Agents; Antibiotics; Antimalarials; Architecture; Area; Artemisinins; Bicycling; Biological; Biology; Chemicals; Chemistry; Clinical; Cobalt; Complex; Cyclization; Development; Diterpenes; Equilibrium; Goals; Hydrazones; Investigation; Laboratories; Lead; Life; Malignant Neoplasms; Methodology; Modernization; Natural Products; Nature; Neurologic; Organic Chemistry; Paclitaxel; Polyenes; Process; Production; Research; Savings; Structure-Activity Relationship; Synthesis Chemistry; Terpenes; Time; Work; analog; bioactive natural products; chemical synthesis; design; empowered; innovation; novel; pre-clinical; programs; small molecule

Project Summary Polycyclic terpenoid natural products are endowed with a broad range of medicinally relevant biological activities. Taxol and artemisinin are two premier examples of life-saving terpenoids; the former is used clinically to treat several different cancers, while the latter is a critical antimalarial agent used worldwide. Chemical synthesis approaches to natural products provide opportunities to make compounds that might be scarcely available from nature, to generate analogues that are only available by total synthesis, and to make probe molecules for increased understanding of the underlying biology. A balance of innovative strategy and new chemical methodology promises efficient syntheses that can serve to answer important biological questions that often can only be probed with small molecules. As part of our laboratory’s long-term goal to enhance efficiency in the synthesis of complex natural products to facilitate important studies in biology, the objective of the proposed research program is to develop concise and creative synthesis designs and empowering methodological advances to permit access to many bioactive diterpenoid natural products. The rationale for this work is that synthetic chemistry is critical to the development of natural product “hit molecules” into legitimate preclinical lead compounds by analogue production, by identification of structure-activity relationships, by the synthesis of chemical probe molecules for mechanism of action studies, and more. An efficient total synthesis of targeted natural products provides a platform from which to address each of these key areas of research. The proposed research is significant because chemical synthesis will provide access to a broad range of biologically important secondary metabolites and analogues with which to interrogate key processes; at the same time, the underlying synthesis designs and methodologies will lead to vertical advancement of the field of organic chemistry. These contributions are innovative by virtue of the chemistry-driven, multi-faceted investigations into the biological activity of diterpenoids with immunosuppressive, antiviral, antibiotic, and neurological activity; the development of new stereocontrolled polyene cyclization strategies to access polycyclic diterpenoid natural products; and the elaboration of new radical bicyclization strategies to make complex architectures relevant to bioactive natural products.

项目概要 多环萜类天然产物具有广泛的药用相关生物活性 紫杉醇和青蒿素是挽救生命的萜类化合物的两个主要例子；前者在临床上使用。 治疗多种不同的癌症，而后者是全世界使用的重要抗疟药物。 天然产物的合成方法为制造几乎不可能的化合物提供了机会 从自然界中获得，生成只能通过全合成获得的类似物，并制备探针 分子以增加对基础生物学的理解创新策略和新策略的平衡。 化学方法有望有效合成，可以回答重要的生物学问题 通常只能用小分子来探测。 作为我们实验室提高复杂天然物质合成效率的长期目标的一部分 产品以促进生物学的重要研究，拟议研究计划的目标是开发 简洁和创造性的综合设计，并赋予方法论进步，以允许访问许多 这项工作的基本原理是合成化学对于生物活性二萜天然产物至关重要。 通过类似化合物将天然产物“热门分子”开发成合法的临床前先导化合物 通过识别结构-活性关系、通过合成化学探针分子进行生产 作用机制研究等。目标天然产物的有效全合成提供了一种方法。 解决这些关键研究领域的平台。 拟议的研究意义重大，因为化学合成将提供广泛的途径 生物学上重要的次生代谢物和类似物，用于研究关键过程； 同时，底层的合成设计和方法将导致该领域的垂直进步 这些贡献是化学驱动的、多方面的创新。 研究二萜类化合物的免疫抑制、抗病毒、抗生素等生物活性 神经活动；开发新的立体控制多烯环化策略以获取 多环二萜类天然产物；以及新的自由基双环化策略的阐述； 与生物活性天然产物相关的复杂结构。